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End of life and palliative care has improved in recent decades but the psychopharmacological options available to clinicians and patients in these contexts remain limited. In particular, psychological factors such as depression, existential distress, and well-being remain challenging to address with current medications. Here, we review recent research on the use of psychedelics in clinical settings with a particular focus on patients with life-threatening diagnoses. We propose that psychedelics may provide clinicians with an additional psychopharmacological treatment in the context of end of life and palliative care.
The Potential of Psychedelics for End of Life
and Palliative Care
David B. Yaden , Sandeep M. Nayak , Natalie Gukasyan ,
Brian T. Anderson , and Roland R. Grifths
1 Contemporary End of Life and Palliative Care
2 Classic Psychedelics
3 Psychedelics in Palliative Care and End of Life Contexts
4 Clinical Considerations for Psychedelics in End of Life and Palliative Care
5 Conclusion
Abstract End of life and palliative care has improved in recent decades but the
psychopharmacological options available to clinicians and patients in these contexts
remain limited. In particular, psychological factors such as depression, existential
distress, and well-being remain challenging to address with current medications.
Here, we review recent research on the use of psychedelics in clinical settings with a
particular focus on patients with life-threatening diagnoses. We propose that psy-
chedelics may provide clinicians with an additional psychopharmacological treat-
ment in the context of end of life and palliative care.
Keywords Psychedelics · Psilocybin · End of Life · Palliative care · Psychiatry
D. B. Yaden (*), S. M. Nayak, and N. Gukasyan
Department of Psychiatry and Behavioral Sciences, Center for Psychedelic and Consciousness
Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
B. T. Anderson
Department of Psychiatry & Behavioral Sciences, Zuckerberg San Francisco General Hospital,
UCSF, San Francisco, CA, USA
R. R. Grifths
The Oliver Lee McCabe, III Professor in the Neuropsychopharmacology of Consciousness,
Department of Psychiatry and Behavioral Sciences, Center for Psychedelic and Consciousness
Research, Department of Neuroscience, Johns Hopkins University School of Medicine,
Baltimore, MD, USA
©The Author(s), under exclusive license to Springer Nature Switzerland AG 2021
Curr Topics Behav Neurosci
Medical advances have made it possible to better manage many of the discomforts
involved in dying, but there are still few medications available to address the
accompanying psychological distress. In Being Mortal (2014), physician Atul
Gawande argues that contemporary society may be somewhat historically anoma-
lous insofar as there are few well-known contemporary norms or guidelines to
dealing with the psychological side of dying. Gawande points to the historical
examples of books called Ars Moriendi (Art of Dying; Shinners 1997) that were
popular in medieval Europe as well as the Tibetan Book of the Dead and the
Egyptian Book of the Dead that each provide cultural forms of instruction on how
to accept the psychological aspects of dying. Gawande (2014,2016) observes that
the modern hospice movement provides psychological support at end of life through
an interdisciplinary clinical team who are tasked with holistically addressing the
biopsychosocial aspects of dying.
Such services both increase the quality of life and extend life in several terminal
illnesses (Connor et al. 2007), contrary to impressions that hospice care reduces
longevity (i.e., giving up). Despite their demonstrated value (for a review, see
Connor et al. 2007), these services are chronically underutilized (Gawande 2016).
The proliferation of hospice services resulted in the broader palliative care move-
ment, a specialty focused on reducing suffering and improving well-being for
patients with serious, chronic, or life-threatening illnesses or injuries in general
(WHO 2011). End of life and palliative care (EOLPC) is a quickly growing medical
specialty, which addresses pain and symptom management among other
biopsychosocial concerns (Aziz et al. 2013).
EOLPC, while valuable, is limited by the psychopharmacological treatments
available. Here, we review research on the efcacy of psychedelic treatments in
the context EOLPC. A number of clinical trials with psilocybin have found
decreased depression and anxiety as well as increased well-being in psychologically
distressed patients who had a life-threatening diagnosis. In this chapter, we suggest
that psychedelics could provide a novel psychopharmacological treatment capable of
reducing psychological distress and supporting the psychological well-being of
actively dying patients and, more generally, in those receiving palliative care.
1 Contemporary End of Life and Palliative Care
End of life care represents a serious economic issue in contemporary healthcare and
poor care can be a source of needless suffering for patients (Gawande 2014). In
response to these issues, the now worldwide hospice movement was created by
English nurse Cicely Saunders to address the psychological suffering of actively
dying patients (Connor 1998; Saunders 1978). Despite their value, most patients are
either not being referred or failing to avail themselves of these services until mere
days before death (Finucane 1999). Some of the many institutional, cultural, and
psychological reasons for failing to utilize these services may be due to an inability
of the clinician to accept the seriousness of the diagnosis (or to see ones role as
D. B. Yaden et al.
intervening to prolong life in all cases). Likewise, patients may fail to understand the
implications of their diagnosis or to appreciate their ability to manage aspects of their
own death. Patients may also believe that requesting such services would let their
family down (for a thoughtful discussion, see Feudtner 2009).
The subject of how one wants to die is frequently avoided, but, when asked,
people express denite preferences. In general, people want to be relatively free from
pain, be surrounded by loved ones, and to feel a degree of meaning and well-being
throughout the dying process (e.g., Singer et al. 1999). When patients, family
members, physicians, and other care providers were surveyed about what is valued
most while dying, all four of these groups indicated at rates above 90% that freedom
from both pain and anxiety were important attributes of end of life care (Steinhauser
et al. 2000). A substantial subset of these patients also indicated the importance of
addressing religious, spiritual, and existential concerns and well-being (Steinhauser
et al. 2000). Additionally, most people say that they want to engage in meaningful
discussions with loved ones and feel a sense of meaning, but many people experi-
ence psychological suffering that prevents such interpersonal connection (e.g.,
Gruneir et al. 2007).
There are a number of psychological services available to address distress in
palliative care patients, such as psychotherapy, social services, access to chaplains,
and integrative medicine modalities (Gawande 2014,2016). In addition to psycho-
therapies like cognitive-behavioral therapy (CBT) and acceptance and commitment
therapy (ACT), there are several manualized, evidence-based psychotherapies avail-
able that are tailored to the needs of EOLPC patients, such as existential interven-
tions focused on meaning and purpose (Bauereiß et al. 2018; Park et al. 2019) and
dignity therapy (Li et al. 2020). While effective to varying extents, these psychoso-
cial treatments could be complemented by psychopharmacological treatments to
enhance outcomes.
In addition to psychosocial therapies, psychopharmacological treatment currently
provides an important but understudied part of end of life care. Standard of care calls
for individualized assessment of treatment needs in terms of pain management,
depression, anxiety, appetite, nausea, and drowsiness (Bruera et al. 1991). Opioids
are routinely used for pain management (Quigley 2008). Cannabinoids such as
dronabinol may be used to stimulate appetite, reduce nausea, and mitigate anxiety
(Mücke et al. 2018). Commonly used drugs for these indications include serotoner-
gic antidepressants, sedative hypnotics, stimulants, and neuroleptics (Candy et al.
2012; Ostuzzi et al. 2018) (for a review, see Grassi and Riba 2014). Studies of
antidepressants in palliative care populations demonstrate small to moderate effect
sizes (e.g., Rayner et al. 2011).
In general, existing pharmacotherapies can produce some symptomatic relief for
patients, but treatment often involves unwanted side effects such as decreased levels
of alertness, memory problems, and impaired coordination (Grassi and Riba 2014).
While the pharmacotherapies available in end-of-life contexts are largely effective at
managing pain, they are less effective at managing depression (Grassi and Riba
2014). Furthermore, existential distress and patient well-being are currently only
The Potential of Psychedelics for End of Life and Palliative Care
indirectly impacted by existing medications to a small degree. Additional psycho-
pharmacological treatments would be valuable in the EOLPC context.
2 Classic Psychedelics
Classic psychedelic drugs (previously called hallucinogens) may prove capable of
effectively addressing psychological needs in end of life care. The psychedelics are a
group of compounds whose action are mediated at the 5-HT
receptor and that
produce substantial changes in perception, affect, and cognition, often accompanied
by a profound sense of personal meaning (Nichols 2016; Vollenweider and Preller
2020). The best known of these compounds are psilocybin, LSD, DMT (and the
DMT-containing plant brew ayahuasca), and mescaline. Psychedelics have been
used in ritual and religious contexts across a number of cultures over hundreds if not
thousands of years (Schultes and Hofmann 1992). Psychedelics were studied in the
1950s and 1960s before burdensome governmental regulations halted research until
around the year 2000 (Johnson et al. 2019).
In this review, we will focus on psilocybin which has been studied more than
other classic psychedelics in clinical trials. Psilocybin (4-phosphoryloxy-N,N-
dimethyltryptamine) is generally similar to serotonin (5-hydroxytryptamine) with
regard to chemical structure and binding activity (Nichols 2016). Psilocybin is
generally safe, well-tolerated and has limited addiction or abuse potential (Johnson
et al. 2019; Nutt et al. 2010; Vollenweider and Preller 2020; Nichols 2016).
Although physically safe, psilocybin experiences can be extremely psychologically
challenging. Some people rate their psilocybin experiences among the most chal-
lenging of their life; however, these same individuals may nevertheless claim that the
experience was meaningful and benecial (Carbonaro et al. 2016). In clinical
settings with therapeutic support, persisting adverse effects have been very limited
(Johnson et al. 2019).
The subjective states associated with psilocybin have been characterized a variety
of different ways, with increasing convergence across psychometric self-report
instruments and qualitative research. The Five-Dimensional States of Consciousness
(5-DASC; Dittrich et al. 2010; Studerus et al. 2011) assesses several dimensions of
changes to subjectivity that occur from psilocybin, including oceanic boundlessness,
anxious ego dissolution, and complex imagery. Among the most therapeutically
relevant mental states that psilocybin produces can be more parsimoniously
described as a mystical-typeexperience, an altered state of consciousness classi-
cally described by William James (1902) and elaborated by other scholars such as
Stace (1960; for a review, see Yaden et al. 2017a). The mystical experience is most
frequently measured in psychedelic research using the Mystical Experience Ques-
tionnaire (MEQ30: Barrett et al. 2015), which includes sub-scales to measure a sense
of unity, reverence, and authoritative truth, positive emotions, transcendence of time/
space, and ineffability.
D. B. Yaden et al.
Psilocybin may also produce experiences of therapeutic relevance characterized
as psychological insight (Carbonaro et al. 2020; Davis et al. 2020a,b) and which can
be assessed with the Psychological Insight Questionnaire (Davis et al. 2020c).
Notably, the majority of participants at Johns Hopkins who have experienced
high-dose psilocybin in clinical research report that this experience is among the
most meaningful of their entire lives (Grifths et al. 2006,2011,2016,2018).
Overall, there is substantial evidence that the subjective effects of psychedelics are
an important factor in their therapeutic effects (see Yaden and Grifths 2020).
Among the rst studies in the contemporary era of clinical psychedelic research
was one that administered psilocybin to healthy psychedelic-naïve participants and
examined changes to well-being (Grifths et al. 2006). This study compared psilo-
cybin to an active control (methylphenidate) condition in a randomized controlled
trial (RCT). Results from this study showed large improvements in various measures
of well-being such as mood, life satisfaction, relationships, and meaning, which
persisted for more than a year, and were mediated by the degree of psilocybin-
associated mystical experience (Grifths et al. 2006,2008).
In addition to the aspects of well-being mentioned above, in a number of clinical
trials with psilocybin, participants have reported enhanced spiritual well-being as a
persisting positive effect from their experience (Grifths et al. 2006,2008,2011,
2016,2018). The improvements to spiritual forms of well-being is of particular
relevance for end of life contexts, as patients report preferring that this psychological
domain is addressed while dying (Steinhauser et al. 2000). Spirituality has been
dened in a number of ways, and while religious and otherwise supernatural
concepts are commonly part of such denitions, supernatural beliefs need not
necessarily be part of spirituality (Yaden et al. 2018,2021a,b). For example, the
Death Transcendence scale (Hood and Morris 1983) measures the extent to which
one believes that ones self will survive beyond bodily death through several
different possible means: the memories of family and friends, the work that one
has contributed to society, by becoming part of nature, religious/spiritual concep-
tions of the afterlife, and/or through a sense of unity with all things. This measure is
one way of conceptualizing well-being and a healthy cognitive mindset regarding
ones own death in a way that could be considered broadly spiritualbut without
necessarily including supernatural concepts. Grifths et al. (2011,2018) showed that
a measure of death transcendence was increased after psilocybin.
Psilocybin has shown promise for treating several disorders spanning several
diagnostic categories. An open-label trial (N¼26) demonstrated initial safety and
feasibility of addressing treatment-resistant depression with up to 25 mg of oral
psilocybin with psychological support (Carhart-Harris et al. 2018). A subsequent
RCT (N¼24) showed marked decreases in depression among moderately to
severely depressed participants compared to a waitlist control using a similar
intervention (Davis et al. 2020b). A more recent head-to-head RCT (N¼59)
provided data suggesting that psychological support plus two doses of psilocybin
25 mg was not superior than psychological support plus daily escitalopram (a widely
used serotonin reuptake inhibitor) on the primary endpoint assessment (Carhart-
Harris et al. 2021). While the secondary outcomes favored psilocybin, these were not
The Potential of Psychedelics for End of Life and Palliative Care
corrected for multiple comparisons so must be cautiously interpreted as exploratory
ndings (Carhart-Harris et al. 2021). There appears to be some trans-diagnostic
efcacy with psilocybin, as preliminary data also suggest the potential for demon-
strating efcacy in the treatment of substance use disorders (Johnson et al. 2014;
Bogenschutz et al. 2015) and possibly obsessive-compulsive disorder (OCD)
(Moreno et al. 2006).
In summary, psychedelics are a class of generally well-tolerated and largely
non-addictive psychoactive substances that have demonstrated therapeutic or other-
wise positive effects under a number of experimental conditions. There is evidence
of potential efcacy across a range of psychiatric disorders and psychedelics are
currently being tested for a wider range of applications, including EOLPC contexts.
3 Psychedelics in Palliative Care and End of Life Contexts
Beyond increasing well-being in healthy volunteers and reducing mood and sub-
stance use disorders in clinical populations, psychedelics have been specically
examined in the context of coping with a life-threatening cancer diagnosis (Grob
et al. 2011; Grifths et al. 2016; Ross et al. 2016). Thus, there is evidence bearing
directly on our primary topic, which we review in more detail below.
Palliative care and end of life contexts were among the rst considered clinical
use cases of psychedelics in the previous wave of research (Kast 1962,1964; Cohen
1965; Pahnke 1969; Fisher 1970; Grof et al. 1973; Richards et al. 1977). Kast (1966,
1967) conducted the rst two studies of LSD in patients who were terminally ill. In
the rst, 80 patients with terminal cancer and a life expectancy of weeks to months
were administered 100 mcg IM LSD under open-label conditions (Kast 1966).
Patients reported an improvement in mood that persisted about 10 days before
declining again. A follow-up study involved treatment of 128 patients with similar
inclusion criteria and design (Kast 1967). Several were quite ill inpatients, with six
dying in the one-week observation period before drug administration. This follow-up
study showed a transient elevation of mood, and improved attitudes toward death
that were evident at 3 days, but not 10 days (Kast 1967).
Grof et al. (1973) reported on 31 cancer patients with at least 3 months life
expectancy who received open-label LSD PO 200500 mcg under supportive
conditions with preparatory and integration sessions. This report showed statistically
signicant baseline to post-treatment improvements in depression, fear of death, and
isolation following the experience, but did not assess how durable these were.
In the contemporary era of psychedelic research (see Table 1), Gasser et al. (2014)
performed the only modern trial of LSD in patients with diagnoses of life-threatening
illnesses. Patients were required to have an advanced-stage potentially fatal illness
with a probability of survival >6 months and meet criteria for a DSM-IV anxiety
disorder or score 40 on either the state or trait scale of the State-Trait Anxiety
Inventory. Of 12 patients, ve met criteria for GAD, 6 for MDD, 1 for dysthymia,
1 for PTSD, and 2 for panic disorder (these were not mutually exclusive). Patients
D. B. Yaden et al.
Table 1 Psychedelic studies relevant to end of life and palliative care
Study Participants Design
Drug condition
(s) Primary outcomes
Grob et al.
Axis 1 diagnoses:
acute stress disorder,
GAD, anxiety disor-
der due to cancer,
adjustment disorder
Axis 3 diagnoses:
advanced-stage can-
cer (100%)
(0.2 mg/kg)
Niacin 250 mg
Feasibility and
safety: mild
increases in heart
rate and blood pres-
sure during psilocy-
bin session. No
signicant differ-
ences before cross-
over in BDI, STAI,
or POMS at 2 weeks
et al.
Axis 1 diagnoses:
GAD (54.5%); MDD
(63.6%); panic dis-
order (27.3%); dys-
thymia (18.2%);
PTSD (8.3%)
Axis 3 diagnoses:
life-threatening dis-
eases including met-
astatic carcinomas
(N¼50%), other
(N¼17%), celiac
disease (8%),
Parkinsons disease
(8%), Bechterews
disease (8%)
active placebo-
LSD 200 μg
LSD 20 μg
At 2 months post
rst session, 200 μg
LSD group had:
reduction in trait
anxiety (p ¼0.03,
d¼1.1), reduction
in state anxiety
(p ¼0.021, d ¼1.2)
Ross et al.
Axis 1 diagnoses:
adjustment disorder
(90%); GAD (10%)
Axis 3 diagnoses:
stage III or IV cancer
(62%); other malig-
nancy (38%)
active placebo-
21 mg/70 kg
Niacin 250 mg
Prior to crossover,
reductions in the
following measures
compared to pla-
cebo group
(Cohens d effect
sizes at 1-day and
7-weeks post ses-
sion): HADS
(d ¼1.4 and 1.4);
BDI (d ¼1.1 and
0.8); STAI state
(d ¼1.2 and 1.2);
STAI trait (d ¼1.0
and 1.3)
et al.
Axis 1 diagnoses:
adjustment disorder
(22/51); dysthymia
(5/51); GAD (5/51);
MDD (14/51); dual
Psilocybin low
dose (1 or 3 mg/
70 kg) psilocybin
high dose (22 or
30 mg/70 kg)
At 1 week post ses-
sion 1, high-dose
rst group had sig-
nicant decreases in
all measures includ-
The Potential of Psychedelics for End of Life and Palliative Care
were randomized to two sessions of 200 mcg or 20 mcg LSD. Those who received
active placebo had the option to later receive open-label 200 mcg LSD. The study
showed signicant decreases in anxiety within the high-dose group (n¼8) from
pretreatment to the 2-month follow-up with a large effect size of 1.1. In contrast, the
low dose group (n¼4) demonstrated an increase in anxiety over that same time
period. Between the two groups, state anxiety was statistically signicantly lower in
the high-dose group and trait anxiety was non-signicantly lower at 2 months.
In contemporary research with psilocybin, at UCLA, Grob et al. (2011)
conducted a study with patients who had been diagnosed with advanced-stage
terminal cancers (prognoses of 6 months to 1 year) who also had DSM-IV diagnoses
of acute stress disorder, GAD, anxiety disorder due to cancer or adjustment disorder
with anxiety. The study was a placebo-controlled RCT within-subject crossover with
12 participants. Niacin was used as placebo and 0.2 mg/kg psilocybin (14 mg for a
Table 1 (continued)
Study Participants Design
Drug condition
(s) Primary outcomes
diagnosis GAD +
depressive disorder
Axis 3 diagnoses:
stage III or IV cancer
(d ¼1.0), BDI
(d ¼1.4), HAM-A
(d ¼1.2) at
6 months post base-
line, the entire group
(collapsed across
conditions) had sig-
nicant decreases in
all measures includ-
(d ¼3.0), BDI
(d ¼1.6), HAM-A
(d ¼3.4)
et al.
N¼18 (all men
50 years old)
DSM-5 diagnoses:
GAD (7/18); MDD
(5/18); panic disor-
der (3/18); borderline
personality disorder
Current general
medical condition:
HIV (18/18), meta-
static malignancy
Preparation and
done as group
0.3 mg/kg or
0.36 mg/kg po
17/18 completed
intervention with
1 participant
discontinuing treat-
ment due to a study-
related adverse
event. Zero study-
related serious
adverse events were
detected. Pre-post
(baseline to
3 months) resulted
in a clinically sig-
nicant change in
¼0.47, 90% CI
D. B. Yaden et al.
70 kg person a modest dose) was used as the active dose. While this pilot study
established the safety of treating anxiety in advanced cancer patients with oral
psilocybin, there were no statistically signicant group differences in anxiety or
depression at follow-up timepoints.
At Johns Hopkins, Grifths et al. (2016) conducted a larger study (N¼51) also in
a population of patients who had received a life-threatening cancer diagnosis. This
trial included patients with an active cancer (e.g., stage III or IV) with a poor
prognosis or disease progression or recurrence (n¼33) or the possibility of
recurrence (n¼18). In addition, they had to have a DSM-IV diagnosis of GAD,
acute stress disorder, PTSD, mild or moderate MDD, dysthymic disorder, or adjust-
ment disorder (with a variety of qualiers). This study compared a very low placebo-
like dose of psilocybin (13 mg/70 kg) to a large dose of psilocybin (2230 mg/
70 kg of body weight). Participants in the high-dose psilocybin group, compared to
the placebo-like control group, reported higher levels of well-being as well as lower
levels of anxiety and depression at 5 weeks. For the majority of the sample (80%),
these changes persisted for 6 months. This study also included observer ratings of the
participant who were blinded to condition, and these observers (e.g., friends, neigh-
bors) reported improvements in participants who had received psilocybin. As has
been reported in several psilocybin trials, self-reported subjective qualities of the
drug administration session predicted positive persisting effects (Yaden and Grifths
At NYU, Ross et al. (2016) conducted a study with participants (N¼29) who had
a life-threatening cancer diagnosis and a DSM-IV diagnosis of acute stress disorder,
GAD, or adjustment disorder with anxiety and/or depression. This study initially
began recruiting terminally ill patients with stage IV cancer, but later broadened the
inclusion criteria to include participants in remission. Ninety percent of patients met
criteria for Adjustment Disorder, and the remaining 10% did for GAD (Ross et al.
2016). In this randomized placebo-controlled crossover study, participants who
received a single session of psilocybin 0.3 mg/kg (e.g., 21 mg for a 70 kg person)
showed reduced anxiety, depression, and cancer-related demoralization, compared
to a niacin placebo group. These ndings persisted at 6-month follow-up. This study
also found improvements in demoralization and hopelessness, constructs highly
relevant to end of life contexts. At about 6 months after the study, the majority of
the sample (70%) indicated that their psilocybin session was among the top ve most
meaningful experiences of their life (Agin-Liebes et al. 2020). Many of these
ndings persisted at 4.5-year follow-up (Agin-Liebes et al. 2020).
At UCSF, Anderson et al. (2020) conducted a pilot study (N¼18, in 3 cohorts of
6) of psilocybin-assisted group therapy for older long-term AIDS survivor (LTAS)
men with moderate-to-severe demoralization. Such individuals live with a chronic
life-threatening illness (i.e., HIV), and many have been acutely ill at various times in
their disease course. Of the enrolled participants, baseline evaluation found that
7 met SCID-5 criteria for GAD, 5 for MDD, 3 for borderline personality disorder,
and 6 had a history of a life-threatening malignancy. Participants underwent
4 pre-drug and 46 post-drug group therapy sessions; psilocybin was administered
individually (without other group members present) at 0.3 mg/kg po to 7 participants,
The Potential of Psychedelics for End of Life and Palliative Care
and then 0.36 mg/kg to the remaining 11 participants. Feasibility was demonstrated
and the intervention was found to be relatively safe with no psilocybin-related
serious adverse events detected in the trial, although 2 unexpected adverse reactions
occurred, 1 participant discontinued treatment due to an adverse reaction, and
14 participants experienced adverse reactions that were at least moderate in severity.
Exploratory pre-post analysis found an improvement in demoralization from base-
line to 3-month follow-up with a mean difference of 5.8 (SD 6.0) and an effect size
of η
¼0.47, 90% CI 0.210.60.
The safety, feasibility, and clinical potential demonstrated in these three recent
studies with psilocybin and one recent study with LSD continue to be evaluated in
ongoing research. It will be important to better understand therapeutic mechanisms,
contraindications, and optimal dosing and psychological context conditions.
Because psilocybin and LSD administration may produce an intense and challenging
psychological experiences with low probability but signicant risks (Johnson et al.
2008; Carbonaro et al. 2016), it is important to proceed with caution. It nevertheless
appears likely, assuming that additional studies result in similar ndings, that
psilocybin may be an effective medication for palliative care and end of life contexts.
4 Clinical Considerations for Psychedelics in End of Life
and Palliative Care
Psychedelic substances have the potential to be a powerful tool in the context of
EOLPC. However, the nature of these substances raises a number of clinical
considerations including both opportunities and challenges.
One area of concern is the risks associated with psychedelics in the context of
common physical symptoms and medical conditions in palliative care populations.
Much of the research on psychedelic-assisted treatment to date, even in patients with
advanced cancer, has been in relatively medically stable individuals who are able to
engage in outpatient care. In a hospice setting, it is possible that psychedelics may
exacerbate nausea or diarrhea, breathlessness, or insomnia. Of particular importance
is whether psychedelics may worsen or precipitate delirium in vulnerable patients.
Barrett et al. (2018) found that global cognitive impairment was not observed in
healthy volunteers at doses of psilocybin up to 30 mg/70 kg. However, decits in
individual cognitive domains were present and dose-dependent. Such impairments
may be more pronounced in palliative care populations who are more at risk of
developing delirium.
A second area of concern is the safety of psychedelics when co-administered with
other medications commonly used at the end of life. Serotonergic antidepressants are
typically contraindicated for co-administration with psychedelics due to the potential
for blunting of subjective effects, as well as a theoretical risk of serotonin syndrome.
Thus, most currently approved protocols require an antidepressant washout period of
45 half-lives prior to administration of a psychedelic. Relatively little is known
D. B. Yaden et al.
about effects of co-administration with other psychotropic drugs but it is likely that
other clinically signicant interactions exist. In healthy volunteers, for example,
haloperidol co-administration with psilocybin was associated with derealization
experiences associated with arousal and anxiety (Vollenweider et al. 1998), and
administration of psychedelics to individuals using lithium has been associated with
seizures (Nayak et al. 2021). Other drugs commonly used in this population that may
be problematic when co-administered with psychedelics include corticosteroids and
stimulants given their risk of precipitating mania, as well as serotonergic agonists
such as ondansetron, since they may theoretically contribute to serotonin syndrome.
While these possible risks have not been systematically evaluated, they are none-
theless worth considering.
A number of other areas of concern remain regarding the generalizability of
psychedelic treatments. While safety guidelines have been provided (Johnson et al.
2008), ongoing research has generally not included individuals with a family history
of psychotic or bipolar disorders. The end of life context and the stressors involved
may provide a particularly stressful context which may increase the likelihood of
adverse responses, although this has not yet been studied. Additionally, there may be
an increased tendency to pair psychedelic treatments with non-evidence-based and
fringe treatments in this context, which should be cautioned against in favor of more
evidence-based treatments (Yaden et al. 2020).
Findings suggest that psychedelics may have analgesic properties, which may
have important implications in palliative care (Castellanos et al. 2020; Kast 1964).
Current mainstay analgesia treatments such as opioid medications have the risk of
sedation and other side effects. Ramaekers et al. (2021) found that LSD acutely
reduced subjective discomfort and pain ratings in healthy volunteers, and that this
effect was achieved with relatively low doses (1020 μg), which might have the
added benet of lower risk of cognitive impairment when compared to high doses.
Psychedelics have been delivered in the context of various psychotherapeutic
modalities and have the potential to be integrated with existing evidence-based
psychotherapies specic to palliative care (Nayak and Johnson 2021). Therapeutic
life review (Keall et al. 2015) and meaning centered therapies (Rosenfeld et al.
2017), for example, closely resemble the life review process commonly done during
preparatory visits in many psychedelic clinical trials.
The end of life context usually involves religious and existential contemplation.
While psychedelics are sometimes claimed to facilitate such contemplations, it is
possible that psychedelics could interfere with this process or appear to some to
interfere with what might be considered a naturalprocess. Indeed, the end of life
context offers a number of bioethical considerations and the possibility of psyche-
delic treatments may further complicate this process. Relatedly, psychedelics present
a number of informed consent concerns. Smith and Sisti (2020) argue that informed
consent for psychedelic treatment should include the possibility of changes to ones
belief system and sense of identity. There are reasons for concern regarding the
possibility of religious/spiritual belief change as a result of using psychedelics from
some self-report surveys (Grifths et al. 2019; Yaden et al. 2017b), although these
The Potential of Psychedelics for End of Life and Palliative Care
do not represent population base rates and other samples have not found such
associations (Yaden and Anderson 2021).
While risks must be weighed, it is also important to consider the positive potential
for psychedelic experiences and the costs of preventing patients from having such
experiences. Earp (2018) argues that psychedelic experiences constitute an impor-
tant form of enhancement that goes beyond the reduction of suffering. Specically,
Earp proposes that psychedelics could promote improvements in ones relationships.
There is good evidence for this, as a number of psychedelic studies report improve-
ments in social relationships (e.g., Grifths et al. 2006,2008,2011,2016,2018;
Pahnke et al. 1970). The relational enhancements provided by psychedelic treat-
ments could open an important window for interpersonal connection with family and
friends during a time that will be the last opportunity for patients to have such
meaningful moments with loved ones. Additionally, Earp (2018) points to other
kinds of enhancements, such as experiences relevant to ones belief system or
worldview. Empirical evidence indicates that experiences resulting from psychedelic
substances are among the most meaningful of ones entire life (e.g., Grifths et al.
2006,2008,2011,2016,2018). Denying such experiences to individuals when,
perhaps, they need them most is a signicant ethical issue to consider.
There are other clinical considerations regarding how psychedelics could be
safely and ethically administered in end of life settings, such as whether there are
evidence-based protocols to safely administer such treatments in end of life contexts.
While it is likely the case that aspects of evidence-based psychotherapies apply
generally to psychedelic treatments (Nayak and Johnson 2021), it remains unclear
how such therapies should be modied when applied to administering psychedelics
in palliative care and end of life contexts.
An important unresolved issue with the prospect of administering psychedelics at
end of life has to do with their specic indication. For example, three of the recent
studies cited above involving psilocybin (Grob et al. 2011; Grifths et al. 2016; Ross
et al. 2016) use medical and psychiatric inclusion criteria that do not fully overlap.
More work is needed in order to specify the indications that are clinically appropriate
and specic for end of life care, and will be acceptable for approval by regulatory
5 Conclusion
In this review, we nd evidence suggesting possible efcacy of classic psychedelics
in treating a variety of psychiatric conditions including end of life distress. Psyche-
delic treatments can provide experiences of meaning and well-being amidst the
process of dying that are highly valued by patients and their families. For some,
this treatment could potentially provide little benet and add additional stress to an
already difcult time, so further research is needed in order to minimize such risks.
For others, such experiences may be among the most important of their entire lives
and could represent a positive intervention with immense psychological value
amidst one of lifes most difcult moments its end.
D. B. Yaden et al.
Acknowledgements Funding: Support for Drs. D. Yaden, S. Nayak, N. Gukasyan, and
R. Grifths through the Johns Hopkins Center for Psychedelic and Consciousness Research was
provided by Tim Ferriss, Matt Mullenweg, Blake Mycoskie, Craig Nerenberg, and the Steven and
Alexandra Cohen Foundation as well as a grant from the Y.C. Ho/Helen and Michael Chiang
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... Recently, after a tangled pathway, the Food and Drug Administration (FDA) not only began to support clinical studies with MDMA and psilocybin, but also assigned them the category of promising therapies for the treatment of depression [34]. Currently, psychedelics research is at Its peak, and the last two years has witnessed an exponential growth in the number of studies, clinical trials, publications, and licenses to research in this area [38][39][40][41]. ...
... Moreover, numerous bioactive alkaloids exert distinctive multi-pharmacological properties which make them suitable candidates in the search for psychotherapeutic agents. Indeed, psilocybin, DMT, and LSD are just a few examples of alkaloids that have prompted the reviving of psychedelic research programs in recent years [10,16,18,40]. Even though the pharmacology of mushroom-derived alkaloids has been under-explored because of governmental and legal restrictions, preliminary preclinical studies have provided encouraging results, and have revealed interesting pharmacological traits of those natural compounds. ...
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Introduction: Psychedelics show promise in treating unipolar depression, though patients with bipolar disorder have been excluded from recent psychedelic trials. There is limited information on the use of classic psychedelics (e. g., LSD or psilocybin) in individuals using mood stabilizers to treat bipolar disorder. This is important to know, as individuals with bipolar depression may attempt to treat themselves with psychedelics while on a mood stabilizer, particularly given enthusiastic media reports of the efficacy of psilocybin for depression. Methods: This study analyzed reports of classic psychedelics administered with mood stabilizers from 3 websites (,, and Results: Strikingly, 47% of 62 lithium plus psychedelic reports involved seizures, and an additional 18% resulted in bad trips while none of 34 lamotrigine reports did. Further, 39% of lithium reports involved medical attention. Most of the lamotrigine reports (65%) but few (8%) of the lithium reports were judged to not affect the psychedelic experience. Discussion: Although further research is needed, we provisionally conclude that psychedelic use may pose a significant seizure risk for patients on lithium.
Several pilot studies have provided evidence supporting the potential of classic psychedelics like psilocybin in the treatment of substance use disorders (SUDs). If larger trials confirm efficacy, classic psychedelic-assisted psy- chotherapy may eventually be integrated into existing addiction treatments such as cognitive behavioral therapy, contingency management, and medication-assisted therapies. Many individuals seeking treatment for SUDs also join twelve-step facilitation (TSF) programs like Alcoholics Anonymous (AA), which are among the most widely available and accessed treatments for alcohol use disorder worldwide. For such individuals, engaging in clas- sic psychedelic-assisted psychotherapy could be seen as controversial, as members of AA/TSF programs have historically rejected medication-assisted treatments in favor of a pharmacotherapy-free approach. We argue that classic psychedelics and the subjective experiences they elicit may represent a special, more compatible case than conventional medications. In support of this claim, we describe Bill Wilson’s (the founder of AA) little known experiences with psychedelics and on this basis, we argue that aspects of classic psychedelic treatments could complement AA/TSF programs. We provide a review of clinical trials evaluating psychedelics in the context of SUDs and discuss their potential large-scale impact should they be ultimately integrated into AA/TSF.
Background Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. Methods In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6. Results A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups. Conclusions On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London’s Centre for Psychedelic Research; number, NCT03429075.) VISUAL ABSTRACT Psilocybin versus Escitalopram for Depression
Psychedelics have shown great promise in modern clinical trials for treating various psychiatric conditions. As a transdiagnostic treatment that exerts its effects through subjective experiences that leave enduring effects, it is akin to psychotherapy. To date, there has been insufficient discussion of how psychedelic therapy is similar to and different from conventional psychotherapy. In this article, we review the shared features of effective conventional psychotherapies and situate therapeutic psychedelic effects within those. We then discuss how psychedelic drug effects might amplify conventional psychotherapeutic processes—particularly via effects on meaning and relationship—as well as features that make psychedelic treatment unique. Taking into account shared features of conventional psychotherapies and unique psychedelic drug effects, we create a framework for understanding why psychedelics are likely to be effective with very diverse types of psychotherapies. We also review the formal psychotherapies that have been adjunctively included in modern psychedelic trials and extend the understanding of psychedelics as psychotherapy towards implications for clinical ethics and trial design. We aim to provide some common conceptual vocabulary that can be used to frame therapeutic psychedelic effects beyond the confines of any one specific modality.